Prostaglandin D2 (PGD2) is a cyclooxygenase (COX)-derived metabolite of arachidonic acid that modulates a wide range of inflammatory processes. Evidence suggests that PGD2 plays an important role in inflammation in the central nervous system and may be involved in the pathogenesis of multiple sclerosis. PGD2 levels are markedly increased in the cerebrospinal fluid (CSF) from multiple sclerosis (MS) patients compared to CSF from other neurological diseases. PGD2 exerts its actions via two G-protein coupled receptors, the classical prostaglandin D2 receptor designated DP and the more recently described chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2 or "DP2"). Each of these receptors is activated by physiologically relevant concentrations of PGD2, but they are distinguished by several criteria, including their activation and blockade by a panel of synthetic ligands, their signal transduction pathways, and their respective tissue distribution. Biological responses to PGD2 are complex and our current understanding of the role of these two receptors in mediating the inflammatory response is incomplete. We hypothesize that activation of the DP receptor plays a critical role in the pathogenesis of MS in a mouse model, experimental autoimmune encephalomyelitis, and theorize that activation of the DP receptor is a critical mediator of the pro-inflammatory effects of PGD2 in MS. To investigate this, we will carry out the following specific aims. In Specific Aim 1, we will characterize a novel signal transduction pathway of PGD2 receptors. In Specific Aim 2, we will determine the role of PGD2 receptors in immune/inflammatory cell function. The PGD2-evoked effects on purified microglia, dendritic cells and T-cell populations will be examined. In Specific Aim 3, we will determine the role of PGD receptors in experimental autoimmune encephalomyelitis using receptor selective ligands and transgenic mouse models. In Specific Aim 4, we will examine the expression of COX, PGD synthase enzymes and PGD2 receptors in MS patients. Demonstration of a critical role for PGD2 receptor subtype(s) in the pathogenesis of MS will identify a novel therapeutic target.